Sustained delivery of bioactive agents, especially peptide- and protein-based drug therapies, has been achieved through the use of biodegradable polymeric implants. Traditionally, this technology has involved surgical implantation of a polymeric monolith containing a suspended bioactive agent. Certain complex shapes of these monoliths have been developed to provide a constant release of the bioactive agent over a period of time. This type of release is described as zero-order, as the rate of release is constant with time. Zero-order kinetics are desirable for therapies that require the administration of a constant level of a bioactive agent.
Polymer microspheres encapsulating a bioactive agent can also be used for controlled release and are generally administered by subcutaneous injection. Although their implantation is easier than that of monoliths, the release mechanism of microspheres is rarely zero-order. An example of a microsphere system with a useful release pattern is the system having a solid polymer shell containing a blend of poly(L-lactic acid) and a bock copolymer of poly(ethylene oxide) and poly(propylene oxide) (U.S. Pat. No. 5,330,768). Encapsulation of a bioactive agent in a microsphere, however, can be difficult and expensive. Also, there is a danger of degradation of the bioactive agent due to exposure to high temperatures and denaturing solvents in the encapsulation process.
Drug release from injectable polymeric implants typically involves a mixture of biodegradable polymer and bioactive agent in a biocompatible solvent. The injectable liquid mixture solidifies upon injection into the body to form the implant. Release of the bioactive agent is provided by diffusion of the agent from the polymeric matrix, by degradation of the polymer and subsequent release of the agent into the surrounding environment, or by a combination of these two mechanisms.
Some types of polymeric implant mixtures are characterized by a premature burst release of the bioactive agent. A premature burst is an initial dose of the bioactive agent released from the mixture during or shortly after injection, that exceeds the desired dosage level and is undesirable for many therapies. Premature bursts are most often observed in implant systems that are based on solvents that readily dissolve in water and in systems which have low viscosities and are therefore relatively easy to inject through a small gauge needle.
Implant mixtures which are provided as highly viscous gels can enable delivery of the bioactive agent without a significant premature burst, but these gels typically have high viscosities and are difficult to dispense through a needle. Also, these viscous implant mixtures tend to be less compatible with the aqueous physiological environment and can be susceptible to unwanted adsorption of proteins on the implant.